Mitogen-Activated Protein Kinase p38 modulates Inflammation in Endometriosis

How is p38 Mitogen-Activated Protein Kinase involved in Endometriosis Pathogenesis?

Key Points

Highlight:

• The increased activity of p38 Mitogen-Activated Protein Kinase (MAPK) in endometriotic cells contributes to the pathogenesis of endometriosis by promoting local inflammation, rather than modulating cell survival.

Importance:

• Blocking activity of p38 MAPK by using specific inhibitors may be suitable to relieve inflammation in endometriosis.

What's done here:

• Comparison of p38 MAPK activity in normal endometrium and endometriosis, as well as its roles in cytokine production and cell survival in endometriosis.
• Eutopic and ectopic endometrial samples were obtained from 27 women with endometriosis, and control endometrial tissues from 30 fertile women.
• Samples were analyzed using immunohistochemical studies to determine levels p38 MAPK, as well as its correlation with interleukin 8 (IL-8).
• Cell proliferation and apoptosis were compared between normal human endometrium and endometriosis.
• Assessment of p38 MAPK action on pro-inflammatory cytokine-induced IL-8 and monocyte chemotactic protein (MCP)-1 expression in endometriotic cells.

Data:

• p38 MAPK activity was higher in both eutopic and ectopic endometria than normal endometria.
• The increased of p38 MAPK activity in endometriotic cells correlated with IL-8 expression, but not with apoptosis.
• The inhibition of p38 MAPK activity blocked the induction of IL-8 and MCP-1 secretion in endometriotic stromal cell culture without affecting cell survival.

Limitations:

• Isolation and growing of endometrial cells in culture can be difficult. Thus the authors were not able to thoroughly investigate the causal role of p38 MAPK in regulating proliferation, apoptosis and cytokine secretion comparing normal tissues and endometriosis.
• The information on endometriosis stage and severity were not available.

Lay Summary

The p38 mitogen-activated protein kinase (MAPK) is a serine/threonine kinase, which transduces signals within the cell in response to various environmental stimuli. In doing so, it mediates intracellular signaling of cytokine production, cell proliferation, and apoptosis amongst many other cellular functions. Increased local estradiol (E2) production is an essential characteristic factor for the pathogenesis of endometriosis. The authors previously showed that E2 could induce p38 MAPK activation in endometrial stromal cells, suggesting that local E2 production in endometriosis may cause constant p38 MAPK activation in endometriosis. Thus, in this study, they evaluated the expression of p38 MAPK in normal endometrium from 30 fertile women and eutopic/ectopic endometrium from 27 women with endometriosis. Also, the correlation of the p38 MAPK activity with cytokine (IL-8) levels and cell survival in endometriosis, along with the role of p38 MAPK signaling in mediating pro-inflammatory cytokine-induced IL-8 and MCP-1 production in endometrial stromal cell cultures were investigated. The article is published in the most recent issue of the scientific journal Reproductive Sciences.

The results showed that activated level of p38 MAPK was significantly higher in ectopic implants compared to normal endometrium in late proliferative and early secretory phases. There was a correlation between IL-8 expression and p38 MAPK, while in vitro findings showed that induction of p38 MAPK activity stimulated MCP-1 and IL-8 expression in cultured endometriotic stromal cells. The higher p38 MAPK activity in eutopic and ectopic endometriosis tissues in late proliferative and early secretory tissues compared to the other cycle may be associated with estrogen level. On the other hand, there was no correlation with apoptosis or cell survival, indicating that increased p38 MAPK activity contributes to the pathogenesis of endometriosis by promoting the local inflammatory milieu rather than modulating cell survival.

Although this study did not show the causal role of p38 MAPK activity in the pathogenesis of endometriosis, the data still showed a higher activity of p38 MAPK in endometriosis than normal endometrium during late proliferative and early secretory phases.

"The inhibition of the p38 MAPK pathway may also provide a treatment option for endometriosis-related pain or infertility in the future, since inflammatory environment may also cause decreased oocyte quality and implantation. The molecular mechanism responsible for endometriotic resistance to p38 MAPK inhibitor-mediated inhibition of cell survival is an important subject for future investigation." concluded the authors.

Research Source: https://www.ncbi.nlm.nih.gov/pubmed/28845752